修回日期: 2012-08-16
接受日期: 2012-09-04
在线出版日期: 2012-11-08
原发性硬化性胆管炎(primary sclerosing cholangitis, PSC)是一种慢性胆汁淤积性自身免疫性肝病(autoimmune liver disease, AILD), 以肝内胆管和/或肝外胆管的弥漫性炎症、同心性纤维化、局灶性或节段性狭窄为主要特征, 最终发展至肝硬化或肝衰竭. PSC的发病机制可能涉及遗传易感性、先天性免疫、获得性免疫及EB病毒感染等. 内镜逆行胆管造影、磁共振胰胆管成像、高分辨三维扰相梯度回波序列等技术已用于PSC的影像诊断. 此外, 胆汁和尿液的蛋白质组学分析可能有助于PSC并发胆管癌的早期诊断. 熊去氧胆酸(ursodeoxycholic acid, UDCA)、内镜以及肝移植是治疗PSC的方法. 上述最新进展为PSC的诊断和治疗提供了新的思路.
引文著录: 黄颖秋. 原发性硬化性胆管炎的研究进展. 世界华人消化杂志 2012; 20(31): 2978-2985
Revised: August 16, 2012
Accepted: September 4, 2012
Published online: November 8, 2012
Primary sclerosing cholangitis (PSC) is a chronic cholestatic autoimmune liver disease characterized by diffuse inflammation, concentric fibrosis, focal or segmental stricture of intrahepatic and/or extrahepatic bile ducts, which can eventually lead to cirrhosis or hepatic function failure. The pathogenesis of PSC may involve genetic susceptibility, innate or adaptive immunity, and Epstein-Barr virus infection. Diagnostic imaging modalities include endoscopic retrograde cholangiography, magnetic resonance cholangiopancreatography, and high-resolution three-dimensional SPGR. Proteomic analysis of bile and urine may become a new tool for early diagnosis of cholangiocarcinoma in PSC patients. Ursodeoxycholic acid (UDCA), endoscopic therapy and liver transplantation are major treatments for PSC.
- Citation: Huang YQ. Advances in research of primary sclerosing cholangitis. Shijie Huaren Xiaohua Zazhi 2012; 20(31): 2978-2985
- URL: https://www.wjgnet.com/1009-3079/full/v20/i31/2978.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i31.2978
原发性硬化性胆管炎(primary sclerosing cholangitis, PSC)是自身免疫性肝病(autoimmune liver disease, AILD)的一种类型, 以慢性胆汁淤积、胆管弥漫性炎性浸润、纤维化、节段性狭窄为主要特征[1-3], 其临床表现和影像特征与IgG4相关硬化性胆管炎(immunoglobulin G4-related sclerosing cholangitis, IgG4-SC)或胆管癌(cholangiocarcinoma, CC)相似[4]. PSC的发病机制可能涉及自身免疫反应[1], 但因对免疫抑制剂缺乏有效应答, 因此还不能称其为典型的自身免疫性疾病[5]. AILD包括自身免疫性肝炎(autoimmune hepatitis, AIH)、原发性胆汁性肝硬化(primary biliary cirrhosis, PBC)和PSC[6]. 部分AIH可同时具有PSC的临床和病理特征, 称为重叠综合征(overlap syndrome, OLS)[7]. PSC在临床少见, 年发病率约为0-1.3/100 000[8], 常并发炎症性肠病(inflammatory bowel disease, IBD)[1,5]. 此外, 主胆管狭窄的PSC发生CC的风险高达26%[9]. 除肝移植外, 迄今尚无有效治疗终末期PSC的方法[10]. 本文就PSC的最新研究进展概述如下.
1.1.1 HLA与PSC: Bergquist等[11]对678例PSC患者研究发现, 其子女、兄妹及父母的PSC风险较正常对照组显著升高, 其风险比率分别为11.5、11.1和2.3, 提示遗传易感因素在PSC的发病机制中起重要作用. 人类白细胞抗原(human leukocyte antigen, HLA)已被证实与PSC的易感性密切相关[12]. HLAⅠ类分子在全部有核细胞表达, 形成CD8+淋巴细胞的内源性抗原, 在自然杀伤(natural killer, NK)细胞及γδT-淋巴细胞(γδT-lymphocytes)充当抑制杀伤细胞免疫球蛋白样受体(killer immunoglobulin-like receptors, KIRs)的配体[1]. HLAⅡ类分子表达于呈递细胞(presenting cells), 形成CD4+淋巴细胞的外源性抗原[1]. HLA-DR3(DRB1*0301)和HLA-B8(HLA-B*0801)单体型(haplotype)被认为是PSC易感性的重要标志物[1]. 此外, HLA-A1、HLA-C7等位基因也与PSC的易感性密切相关[1]. HLAⅡ类单体型编码的易感性等位基因为HLA-DRB1*0301(DR3)和-DRB1*13(DR6)[1]. PSC与某些HLAⅡ类单体型呈正相关, 包括HLA-DRB1*03、-DQA1*0501、-DQB1*02、-DRB1*15、-DQA1*0102、-DQB1*0602、-DRB1*13、-DQA1*0103及-DQB1*0603, 而与HLA-DRB1*04、-DQA1*03及-DQB1*0302等单体型呈负相关[1]. PSC相对易感性最高的基因为HLA-DRB1*03、-DQA1*0501及-DQB1*02纯合子基因型[1].
1.1.2 非HLA与PSC: Karlsen等[13]研究发现, KIRs和/或HLAⅠ类配体失衡致使抑制减少或激活增加在PSC的发病机制中至关重要. MICA5.1、MICB24、CCR5、MDR1等非HLA基因被证实与PSC的易感性密切相关[1]. 此外, ICAM-1的基因多态性也被证实与PSC的易感性显著相关[12]. Naess等[14]对PSC患者的全基因组关联分析(genome-wide association analysis, GWA)确认的遗传易感基因位点包括2q13、2q35、3p21、4q27和13q31. Srivastava等[15]对992例PSC患者的3p21(MST1)和10p15(IL2RA)位点的GWA分析首次确认了10p15(IL2RA)基因位点的变异, 表明IL-2/IL2RA通路在PSC发病中起重要作用, 并进一步确认了MST1基因的易感性. Folseraas等[16]对1 221例PSC患者的GWA扩展分析发现, 位于lp36的MMEL1和TNFRSF14基因有强烈的潜在致病风险; 位于19q13的FUT2基因对病原体易感性存在变异; 位于19q13染色体rs601338位点的分泌型FUT2基因显著影响PSC患者胆汁微生物菌落的成分. Karlsen等[17]研究显示, 非HLA的变异型与PSC的胆汁体内平衡及炎症通路的调节密切相关, 若根据炎症、胆管上皮细胞功能、纤维化及致癌作用4个方面的遗传易感性将PSC分为相应的亚型对以后的基础和临床研究或许更有价值. Melum等[18]应用GWA对715例PSC患者的单核苷酸多态性(single nucleotide polymorphisms, SNPs)研究进一步证实了非HLA与PSC的相关性, 且至少存在2个额外的非HLA易感基因位点涉及T细胞激活和免疫耐受, 一个辨识成分可能参与PSC的发病机制.
1.2.1 体液免疫与PSC: 业已证实, PSC患者血清中含有多种自身免疫性抗体[19], 包括抗-胆管上皮细胞抗体(Anti-BEC)、抗-中性粒细胞胞浆抗体(ANCA)、抗-核抗体(ANA)、抗-平滑肌抗体(SMA)、抗-酿酒酵母菌抗体(ASCA)、抗-线粒体抗体(AMA)、抗-肝肾微粒体抗体(Anti-LKM)、抗-可溶性肝抗原/肝胰抗原抗体(Anti-SLA/LP)、抗-内皮细胞抗体(AECA)、抗-甲状腺过氧化物酶抗体(Anti-TPO)、抗-肾小球基底膜抗体(Anti-GBM)及抗-谷胱甘肽S-转移酶θ1抗体(Anti-GSTT1)等, 但大多数抗体的特异性较低[19]. ANCA对PSC的特异性相对较高, 包括胞浆型(c-ANCA)和核周型(p-ANCA), 后者又进一步被分为典型p-ANCA和不典型p-ANCA[20]. 逾80%的PSC患者含有不典型p-ANCA, 似乎更具特异性, 主要为IgG抗体[1]. 不典型p-ANCA能识别人中性粒细胞微管蛋白β5同工型(tubulin beta isoform 5, TBB-5)和细菌细胞分裂蛋白(bacterial cell division protein)FtsZ, 这一发现重新引起了人们对微生物在PSC潜在致病机制的兴趣和探讨[20,21]. Terjung等[22]研究发现, p-ANCA直接与TBB-5、FtsZ的交叉反应可能反映了易感人群对肠微生物的异常免疫应答, 提示p-ANCA可能参与PSC的发病机制. Ardesjö等[23]研究证实, Anti-GSTT1对PSC既无特异性, 也非敏感性, 但其在自身免疫性疾病患者的发生频率却显著高于对照组. 此外, 少数PSC患者血清IgG4升高, 且与疾病严重程度相关[24-27]. Navaneethan等[26]发现, 50例PSC患者中10例血清IgG4升高, 且术后生存率显著低于IgG4正常的PSC患者. 此外, 血清IgG4升高的PSC患者可合并系统性淀粉样变性, 而IgG4-SC则无[27]. IgE在PSC发病机制中的作用尚存争议. Hirano等[28]发现, 血清IgE增高的PSC患者其发病年龄高于IgE正常者, 且并发CC的风险降低. 而Navaneethan等[29]研究显示, 19例PSC患者中8例(42.1%)IgE增高, 且发病年龄低于IgE正常者, 但并发CC的风险增高.
1.2.2 细胞免疫与PSC: PSC的发生可能由透过肠黏膜进入门脉循环的细菌或病原体相关分子模式(pathogen-associated molecular patterns, PAMPs)等外源性因素触发[1]. 巨噬细胞、树突状细胞(dentritic cells, DCs)及NK细胞被激活后释放细胞因子, 并使DCs不断持续炎症反应[12]. 此外, 胆管上皮细胞(biliary epithelial cells, BECs)可获得一种粘附分子过度表达的反应性表型, 致使炎性细胞因子、趋化细胞因子及生长因子进一步促进炎症过程[1]. BECs作为胆道系统防御腔内微生物的第一道防线, 通过表达各种病原体识别受体(pathogen recognition receptors), 并使若干细胞内通路激活开启防御过程, 包括产生抗微生物肽、细胞因子、趋化因子及粘附分子[30]. 此外, BECs还能分泌免疫球蛋白A, 通过粘附分子和免疫介质的表达和释放与其他细胞相互作用[30]. PSC患者汇管区可见密集的T细胞浸润, 但T细胞的构成比(CD4/CD8比例)在不同的研究中却迥然不同, 这或许反映了肝内T细胞亚型的分布, CD4细胞更常见于汇管区, 而CD8细胞则在小叶性肝炎区域占优势[1]. CD8+T细胞缺陷在PSC的发病机制中可能起重要作用[31]. CD8+T细胞缺陷可导致其控制的EB病毒(epstein-barr virus, EBV)感染辨识性B细胞(autoreactive B cells), 后者积聚于靶器官产生致病性自身抗体, 并将共刺激残余信号提供给辨识性T细胞, 否则将通过激活诱导凋亡死于靶器官[31].
自身免疫性疾病的某些易感基因可能影响病原体的外显率, 使诱发自身免疫的病毒或细菌反复引发感染[32]. EBV感染已被证实与经常并发AILD的几种自身免疫性疾病有关[32]. EBV感染的作用过去常归因于EBV与自身抗原间的免疫交叉反应, 但近年来提出的EBV感染辨识性B细胞假说被认为是人类自身免疫性疾病的基础[31]. 尽管尚无直接证据表明EBV参与PSC的发病机制, 但已确认EBV与并发或不并发PSC的UC有关[32]. EBV是否介导PSC的发病还有待于进一步研究.
异生物质(xenobiotic)可诱导出胆管炎动物模型, 但常因炎症反应的转瞬即逝而使人们低估和忽视其在PSC发病机制中的作用. 然而, 这种胆管炎症最终可发展至胆管消失综合征(vanishing bile duct syndrome)、胆管纤维化及肝硬化[33]. 因此, 异生物质在PSC发病机制中的作用应引起足够重视.
PSC的典型临床表现为慢性胆汁淤积和皮肤瘙痒[1-3], 主胆管狭窄者并发CC的风险明显增加[9]. 最近, Ngu等[34]完成了一项基于人群的AILD发病率、死亡率及恶性肿瘤发生率的相关研究. 结果显示, PSC队列的风险率为613人/年, 在95%可信区间内, PSC的全因标准化死亡率(standardized mortality ratios, SMRs)为4.1, 肝胆管病因SMRs为116.9, 所有肿瘤标准化发病率(standard incidence ratios, SIRs)为5.2, 肝外肿瘤SIRs为3.0. PSC患者罹患肝癌及其他恶性肿瘤的风险显著增加, 此外, 肝脏相关死亡率也显著增加, 表明当前的治疗措施仍不尽如人意. 约2/3的PSC患者常合并IBD, 尤其是溃疡性结肠炎(ulcerative colitis, UC). Halliday等[35]研究发现, 240例PSC患者中有129例合并UC, 32例合并克隆恩病(Crohn's disease, CD). Ngu等[36]研究发现, 伴发IBD的PSC患者其年龄低于不伴发IBD者, 前者更易并发恶性肿瘤、更需要肝移植、更易死亡, 提示IBD影响PSC患者预后, 但Navaneethan等[37]对167例合并UC和55例未合并UC的PSC患者研究显示, 前者的发病年龄确实明显低于后者(38岁 vs 47岁, P<0.001), 但UC并未影响PSC患者的长期预后. Jørgensen等[38]研究证实, 84%的PSC患者合并IBD, 多数为UC, 少数为CD. 此外, PSC还可合并肝细胞腺瘤(hepatocellular adenomas, HCA)[39]、系统性淀粉样变性[27]、消化道大出血[40]、重症肌无力(myastheniagravis)[41]、直肠非Hodgkin's淋巴瘤(non-Hodgkin's lymphoma)[42]、黄色肉芽肿性胆囊炎(xanthogranulomatouscholecystitis, XGC)[43]、干燥综合征(Sjogren's syndrome, SS)[44]、胆囊黏液腺癌(mucin-producing carcinoma of the gallbladder)[45]、胆囊淋巴瘤(gallbladder lymphoma)[46]以及AIH[7,47]或PBC[48], 即所谓的OLS[49,50]. 上述特征无疑使PSC的临床表现更为复杂. 在某些国家, PSC不仅已跻身于肝移植的最常见人群, 而且也被认为是肝胆恶性肿瘤, 尤其是胆管癌的癌前状态, 合并IBD者并发结肠癌的风险也显著增加[51].
内镜逆行胆管造影(endoscopic retrograde cholangiography, ERC)一直被认为是诊断PSC的金标准[52]. 其影像学特征主要表现为肝内外胆管的多灶性狭窄, 胆管壁僵硬缺乏弹性, 似铅管状, 狭窄上端的胆管可扩张, 呈串珠样表现[52]. ERC不仅用于PSC的诊断, 还可以对完全或不完全闭塞的大胆管行内镜球囊扩张和/或置放支架治疗[53]. 然而, ERC仍有其固有风险, 如急性胰腺炎、胆管炎及十二指肠穿孔[52]. 此外, PSC患者的慢性胆道病变致Oddi氏括约肌屏障缺失, ERC可能导致严重的并发症和慢性复发性胆管炎、肝脓肿及肝功能减退等问题[52]. PSC与IgG4-SC或CC的影像学特征酷似, 及时而准确的鉴别十分重要. Kalaitzakis等[4]研究发现, 尽管ERC诊断PSC的特异性很好, 但敏感性很差, 仅靠ERC尚不能准确与IgG4-SC或CC鉴别. 磁共振成像(magnetic resonance imaging, MRI)及磁共振胰胆管成像(magnetic resonance cholangiopancreatography, MRCP)也是诊断PSC的良好选择[52]. MRI的典型特征为肝脏各叶形态改变及胆管扩张, MRCP则显示胆管狭窄、扩张、呈串珠样或剪枝样改变[52]. 其诊断PSC的敏感性与ERC相似, 但因非侵入性及并发症很低使其更具诊断优势[52]. 最近, Nagle等[54]研究发现, 高分辨三维扰相梯度回波序列(three-dimensional-SPGR)MRI肝胆管成像可用于PSC诊断, 尽管SPGR在某些患者可致肝功能减退, 但对PSC患者极佳的影像质量及胆汁分泌的可视化扫描, 常能提供传统MRCP无法得到的诊断信息. Frydrychowicz等[55]研究显示, 钆塞酸(gadoxetic acid)增强T1加权MRI胆管造影(T1-weighted MRI cholangiography, T1w-MRC)与T2w-MRCP对PSC的诊断相辅相成, 不可替代. T1w-MRC有助于T2w-MRCP的形态学评估并为之提供额外的诊断信息. Kubota等[56]研究显示, 胆管内超声(intraductal ultrasonography, IDUS)有助于PSC与IgG4-SC或CC鉴别. 此外, Alkhawaldeh等[57]研究发现, 以SUVmax>3.9作为恶性肿瘤标准, F-18氟脱氧葡萄糖正电子发射计算机断层扫描(F-18 FDG PET)的半定量分析可提高PSC与CC鉴别诊断的准确性.
PSC的典型组织病理学特征为同心性"洋葱皮"样纤维化, 但因肝穿刺活检组织的阳性率不足10%, 这种典型的组织学改变很难看到, 通常的活检组织仅表现为零星的炎细胞浸润、小叶间胆管扭曲、胆管上皮空泡化、灶性淋巴细胞浸润, 细胞核呈角状或出现不规则空隙. 前已述及, PSC的临床及影像学特征酷似IgG4-SC, 且有20%的PSC患者血清IgG4升高[26], 但二者的组织病理学特征迥然不同. IgG4-SC的汇管区周围组织内可见由成纤维细胞、浆细胞、淋巴细胞和嗜酸性粒细胞组成的特异性纤维炎症结节以及大量IgG4阳性的淋巴细胞、浆细胞浸润, 而PSC则无此特征, 以此可对二者鉴别[58]. 此外, 小胆管PSC(small duct PSC)是PSC的一种特殊类型, 具有典型的胆汁淤积和PSC组织学改变, 但胆管影像正常[59].
PSC合并CC的早期诊断十分困难. Lankisch等[60]研究发现, 胆汁的蛋白质组学分析(proteomic analysis)能准确区别PSC和CC, 这不仅为诊断胆道恶性肿瘤提供了新的思路, 也可能成为未来的一种诊断工具. Reinhard等[61]应用蛋白质组学技术对45例PSC患者研究发现, PSC患者的胆汁S100A9表达比对照组高95倍(P<0.005). 提示, 胆汁S100A9水平是PSC活性的有效标志物. 但此方法的弊端在于胆汁的采集需要侵入性的ERC检查. 因此, Metzger等[62]评估了CC、PSC和良性胆道疾病(benign biliary disorder, BBD)患者的尿蛋白质组学分析. 结果显示, 其敏感性为83%, 特异性为79%. 提示, 尿蛋白质组学分析可准确区别CC、PSC及其他BBD, 并可作为PSC和CC新的非侵入性诊断工具.
熊去氧胆酸(ursodeoxycholic acid, UDCA)是治疗早期或中期PSC的常用药物, 可降低肝功转氨酶、缓解乏力和皮肤瘙痒, 其可能的作用机制包括[63,64]: (1)通过下调MHCI基因表达而抑制炎症反应; (2)通过替代或清除内源性胆酸而保护胆管上皮细胞; (3)通过调节免疫活性细胞重新构建胆汁分泌功能; (4)通过刺激胆管碳酸氢盐分泌拮抗胆汁淤积. 肝细胞摄入UDCA是后续代谢及有效治疗的先决条件[65]. UDCA是否位于肝细胞基底膜的转运蛋白OATP1B1、OATP1B3、OATP2B1及钠牛磺酸盐共转运多肽(Na+-taurocholate co-transporting polypeptide, NTCP)尚不清楚[65]. 为此, König等[65]研究发现, OATP1B1、OATP1B3、OATP2B1、NTCP与人类肝细胞对UDCA的摄取及作用无关. 换言之, UDCA并非位于肝细胞基底膜的转运蛋白. 目前, UDCA治疗PSC的常规剂量尚无定论, 通常采用10-30 mg/(kg•d). 但近年来推荐高剂量UDCA. Imam等[66]应用28-30 mg/(kg•d)对PSC患者治疗发现, 高剂量UDCA导致的不良风险增加仅出现于组织学早期改变或总胆红素正常的患者. Lindström等[67]研究显示, 高剂量UDCA长期治疗并不能阻止合并IBD的PSC患者罹患结直肠癌或异型增生的风险. 此外, 其他药物或许对PSC也有一定治疗作用. Martin等[68]研究发现, 二十二碳六烯酸(docosahexaenoic acid, DHA)致血清DHA增加可使PSC患者碱性磷酸酶显著降低, 提示DHA对PSC有一定辅助治疗作用. Karaahmet等[69]研究认为, 西罗莫司(rapamycin)可减缓PSC的进展. 除此之外, 大量的临床试验尚未证实免疫抑制剂、抗纤维化制剂、抗生素等药物对PSC治疗有效[70].
Chapman等[9]研究发现, PSC患者主胆管狭窄的平均生存期显著低于无主胆管狭窄者(13.7岁 vs 23.0岁), 且生存期的明显差异与前者26%的罹患CC风险密切相关. 因此, 如何延缓或减轻PSC患者的主胆管狭窄是临床医生面临的重要课题. 研究显示, 内镜球囊扩张或置放支架可减轻PSC患者的胆管狭窄、缓解临床症状、改善胆汁淤积引起的酶学改变, 但仅限于胆道梗阻的进展期PSC患者[70].
肝移植(liver transplantation, LTX)是目前终末期PSC患者的唯一有效治疗手段[10]. 在某些国家, PSC已成为LTX的首要适应症[51]. LTX术后的5年生存率接近80%, 但复发问题已越发明显, 大约1/5的PSC患者LTX术后复发(recurrent primary sclerosing cholangitis, rPSC), 还有相当比例的LTX患者因供肝失活而影响其长期生存率[10]. rPSC的发病机制仍不清楚, 但被认为与PSC相似[10]. 排斥和复发或许显示了LTX术后PSC患者供肝所发生的连续免疫反应[10]. 减少rPSC的最可信机制似乎与合并IBD以及LTX术前PSC患者未行结肠切除术而起的保护作用有关[10]. 因此, PSC患者LTX术前不必行结肠切除术似乎非常重要[10].
PSC是一种发病机制尚未十分清楚的AILD, 常合并IBD, 最终至肝硬化或肝衰竭. GWA的应用使PSC更多的易感基因被发现, 对其发病机制的认识有十分重要的意义. 蛋白质组学技术的飞速发展使PSC并发CC的早期诊断似乎成为可能. PSC新的易感基因和特异性诊断标志物的寻找应是目前研究的重点, 而如何减少LTX的术后复发率应是未来努力的方向.
原发性硬化性胆管炎(PSC)是一种不明原因的自身免疫性肝病, 以慢性阻塞性黄疸、肝内外胆管弥漫性炎症、纤维化及狭窄变形为主要特征, 最终导致胆管阻塞、胆汁性肝硬化和肝衰竭. 尽管PSC少见, 但因其临床及影像学特征与另一种自身免疫性疾病IgG4相关硬化性胆管炎(IgG4-SC)十分相似, 近年来已引起国内外学者的关注, PSC的相关研究也取得很多进展.
王刚, 副研究员, 哈尔滨医科大学附属第一医院胰胆外科(普外二科)
全基因组关联分析(GWA)已确认了许多基因位点的遗传易感性, 随着研究的不断深入, 更多的易感基因将被发现, 这对于探讨PSC的发病机制有十分重要的意义.
Lankisch等采用蛋白质组学分析技术准确鉴别PSC和CC, 为胆道恶性肿瘤的早期诊断提供了新的思路.
本文详尽阐述了PSC的发病机制、诊断及治疗取得的最新进展, 提供了大量有价值的信息.
本文全面系统阐述了遗传易感性、体液免疫及细胞免疫在PSC发病机制中的作用, 详尽阐述了PSC的临床、影像、组织病理学以及治疗方面的最新研究进展, 提供了大量有价值的信息, 对PSC的基础与临床研究有重要的指导意义.
胆管消失综合征(VBDS): 指多种原因导致的胆管树破坏而使肝内胆管局灶性或弥漫性消失, 组织学检查无胆管正常结构存在, 临床表现以胆汁淤积为特征.
本文较详尽地阐述了近年来PSC发病机制、诊断及治疗等方面所取得的最新进展, 对指导PSC的基础研究与临床治疗具有重要意义.
编辑:李军亮 电编:鲁亚静
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